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It is well-understood that cell membranes are crowded and complex environments, containing up to 50 % protein by mass [1] and comprised of myriad types of lipid species [2]. Less well understood is the molecular detail of the effects of complexity and crowding on membrane organisation and dynamics. Advances in coarse-grained force fields and computational power mean that large-scale coarse-grained (CG) molecular dynamics (MD) simulations are increasingly being used to gain such understanding [3].To investigate the role of protein crowding and lipid complexity on the organisation and dynamics of mammalian cell membranes, and particularly the effect of protein-lipid interactions on protein and lipid diffusion in crowded membranes, we have performed large CG MD simulations containing over 100 inward rectifier potassium (Kir) channels, which have specific lipid interactions with PIP2, other anionic lipid interactions and cholesterol.Lipid complexity has a marked effect on the clustering behaviour of channels, underlying which are the diffusive properties of different lipid mixtures. Subdiffusion of lipids tightly interacting with Kir channels is also observed, and this subdiffusion is further modulated by protein crowding. By simulating Kir channels in a complex lipid mixture, we can also examine the interplay between PIP2, other anionic lipids and cholesterol interactions. In simulating systems of >100 nm in dimension whilst retaining membrane complexity at a molecular level, we start to move further towards the use of simulation as a computational microscope, and can assess the possibilities using this approach.1. Dupuy and Engelman. Proc Natl Acad Sci USA, 2008 105 (8): 2848–522. Coskun and Simons. Structure, 2011 19(11): 1543–48.3. Chavent, Duncan and Sansom. Curr Op Struct Biol, 2016. 40: 8–16 |
